Abstract

This project examines the physiological effects and the underlying biochemical mechanisms of the action of delta opioid peptide DADLE in cellular survival. In this fiscal year, we found that DADLE completely blocks the dopamine and tyrosine hydroxylase loss induced by a high dose of methamphetamine. The involvement of p53 in this action of DADLE is, however, uncertain. In PC12 cells, DADLE is anti-apoptotic in pM to nM concentrations whereas is cytotoxic in the micromolar range. The anti-apoptotic action of DADLE is related to an increase in the ERK phosphorylation and the cytotoxic action of DADLE is related to the activation of Fas ligand. In CD-1 mice, methamphetamine causes an increase of Bax translocation from cytosol into mitochondria and an increase of mitochondrial cytochrome c release into the cytosol. DADLE blocks the Bax translocation and cytochrome c release caused by methamphetamine. In working isolated rabbit hearts as well as the rat hearts, preconditioning of the isolated preparation with DADLE confers myocardial tolerance to ischemia. This action of DADLE was blocked by a delta-2 opioid receptor antagonist. These results suggest that the underlying protective action of DADLE may involve the alteration of the dynamics of Bax and that DADLE may have important clinical implications against degenerative diseases in the central nervous sytem as well as in the periphery.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Intramural Research (Z01)
Project #
1Z01DA000263-08
Application #
6535472
Study Section
(CNRB)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2001
Total Cost
Indirect Cost

  Institution

Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Tsai, Shang-Yi; Hayashi, Teruo; Su, Tsung-Ping (2005) Picomolar concentrations of hibernation induction delta opioid peptide [D-Ala2,D-Leu5]enkephalin increase the nerve growth factor in NG-108 cells. Synapse 57:179-81
Borlongan, Cesario V; Wang, Yun; Su, Tsung-Ping (2004) Delta opioid peptide (D-Ala 2, D-Leu 5) enkephalin: linking hibernation and neuroprotection. Front Biosci 9:3392-8
Wang, Yun; Chang, Chen-Fu; Morales, Marisela et al. (2003) Diadenosine tetraphosphate protects against injuries induced by ischemia and 6-hydroxydopamine in rat brain. J Neurosci 23:7958-65
Hayashi, Teruo; Su, Tsung-Ping (2003) Chronic [D-Ala2, D-Leu5]enkephalin treatment increases the nerve growth factor in adult mouse brain. Eur J Pharmacol 464:237-9
Hayashi, Teruo; Tsao, Li-I; Su, Tsung-Ping (2002) Antiapoptotic and cytotoxic properties of delta opioid peptide [D-Ala(2),D-Leu(5)]enkephalin in PC12 cells. Synapse 43:86-94
Bolling, S F; Badhwar, V; Schwartz, C F et al. (2001) Opioids confer myocardial tolerance to ischemia: interaction of delta opioid agonists and antagonists. J Thorac Cardiovasc Surg 122:476-81
Wang, Y; Hayashi, T; Chang, C F et al. (2001) Methamphetamine potentiates ischemia/reperfusion insults after transient middle cerebral artery ligation. Stroke 32:775-82
Borlongan, C V; Zhou, F C; Hayashi, T et al. (2001) Involvement of GDNF in neuronal protection against 6-OHDA-induced parkinsonism following intracerebral transplantation of fetal kidney tissues in adult rats. Neurobiol Dis 8:636-46
Borlongan, C V; Su, T P; Wang, Y (2001) Delta opioid peptide augments functional effects and intrastriatal graft survival of rat fetal ventral mesencephalic cells. Cell Transplant 10:53-8
Hayashi, T; Hirata, H; Asanuma, M et al. (2001) Delta opioid peptide [D-Ala2, D-Leu5]enkephalin causes a near complete blockade of the neuronal damage caused by a single high dose of methamphetamine: examining the role of p53. Synapse 39:305-12

Showing the most recent 10 out of 17 publications